Benzene exposure promotes neuroinflammation and metabolic dysregulation

接触苯会促进神经炎症和代谢失调

• 批准号: 10597556
• 负责人: Marianna Sadagurski
• 金额: $ 38.76万
• 依托单位: WAYNE STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2027-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10597556
• 关键词: Ablation; Affect; Age; Air Pollution; Astrocytes; Attention; Benzene; Benzene Exposure; Cells; Chronic; Detergents; Development; Dose; Energy Metabolism; Environment; Environmental Exposure; Environmental and Occupational Exposure; Etiology; Exposure to; Food; Future; General Population; Genetic; Glucose; Goals; Health; Health Policy; Histology; Homeostasis; Human; Hyperglycemia; Hypothalamic structure; Immune; Impairment; In Situ Hybridization; In Vitro; Individual; Inflammation; Inflammatory; Inflammatory Response; Insulin; Insulin Resistance; Intervention; Knockout Mice; Leptin; Link; Literature; LoxP-flanked allele; Mediating; Meta-Analysis; Metabolic; Metabolic Diseases; Metabolic dysfunction; Metabolism; Microglia; Modeling; Modernization; Molecular; Morphology; Mus; Neuroglia; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Occupational; Outcome; Oxidative Stress Induction; Paint; Pathology; Pathway interactions; Peripheral; Physiological; Pollution; Predisposition; Pregnant Women; Public Health; Publishing; Regulation; Research; Risk; Rodent; Role; Shapes; Signal Pathway; Signal Transduction; Societies; System; Testing; Time; Tissues; Tobacco smoke; Underrepresented Minority; Water; Work; biological adaptation to stress; blood glucose regulation; conditional knockout; cost; design; e-cigarette aerosols; endoplasmic reticulum stress; exhaust; exposure route; exposure to cigarette smoke; glial activation; glucose metabolism; glucose monitor; human model; immunological status; in vivo; insight; insulin signaling; insulin tolerance; male; mouse model; neuroinflammation; new therapeutic target; novel; prevent; response; systemic inflammatory response; urban area; urinary; volatile organic compound; young adult

ABSTRACT Benzene is a prominent volatile organic compound (VOCs) that is present in water, food, paint, detergents, vehicle exhaust, tobacco smoke, and e-cigarette vapors. Exposure to low doses of environmental benzene in urban areas has been implicated in increasing the risk for metabolic dysfunction across all ages. However, a direct link between exposure to low-dose benzene and metabolic homeostasis is not yet established. Using the limited available literature on environmental exposure to benzene and its metabolic outcomes, we performed a preliminary meta-analysis and found a positive association between exposure to benzene and metabolic impairments. Our preliminary studies provide strong evidence that chronic exposure to benzene at varying low doses, modeling human exposure routes, induces significant insulin resistance and hyperglycemia in rodents. Neuroinflammation is increasingly recognized as one of the causal factors in the pathology of metabolic diseases. Glial cells (microglia and astrocytes) have recently garnered specific attention for their role in neuroinflammatory responses in metabolic disorders. Microglia, produce various pro-inflammatory molecules that are critical for the development of peripheral metabolic imbalance and insulin resistance via hypothalamic inflammation. We show that benzene exposure at several low doses relevant to occupational and environmental exposure promotes robust hypothalamic glial activation and elevation in the hypothalamic inflammatory IKKβ/NF-κB signaling pathway followed by the induction of endoplasmic reticulum (ER) stress response. Our central hypothesis is that benzene-induced changes in microglial function and IKKβ/NF-κB signaling underlie changes in whole-body glucose homeostasis and metabolic responses. This hypothesis will be assessed with a novel murine model of air-pollution combining molecular, genetic, and physiological approaches designed to manipulate both the number and the inflammatory activation state of resident microglia in the following Specific Aims: 1) To determine the contribution of exposure to low benzene concentrations to neuroinflammation and metabolic regulation; 2) To determine the role of central IKKβ/NF-κB inflammatory mechanism in a benzene-induced metabolic imbalance: 3) To determine the cellular and molecular interplay between microglia neuroinflammation and ER stress response triggered by benzene exposure. The proposed research will, for the first time, directly assess the role of benzene-induced changes in glial function and inflammatory signaling in regulating whole-body metabolism. Such a study will be of importance for shaping public health policy regarding benzene exposure and its role in predisposition to develop metabolic diseases.

摘要 苯是一种主要的挥发性有机化合物（VOCs），存在于水，食品，油漆， 清洁剂、汽车尾气、烟草烟雾和电子烟蒸汽。接触低剂量 城市地区的环境苯与增加代谢性疾病的风险有关。 所有年龄段的功能障碍。然而，暴露于低剂量苯和 代谢平衡尚未建立。利用有限的可用文献， 环境暴露苯及其代谢结果，我们进行了初步的 荟萃分析发现，苯暴露与代谢之间存在正相关， 损伤我们的初步研究提供了强有力的证据表明长期接触苯 在不同的低剂量下，模拟人体暴露途径，诱导显著的胰岛素抵抗 和高血糖症。神经炎症越来越多地被认为是 代谢性疾病的病理因素。神经胶质细胞（小胶质细胞和星形胶质细胞）最近 因其在代谢紊乱的神经炎症反应中的作用而受到特别关注。 小胶质细胞，产生各种促炎分子，这些分子对发展中国家的疾病至关重要。 外周代谢失衡和胰岛素抵抗通过下丘脑炎症。我们表明 几种低剂量苯暴露与职业和环境有关， 暴露促进下丘脑神经胶质细胞的强烈活化和下丘脑神经胶质细胞的升高 炎症性IKKβ/NF-κB信号通路随后诱导内质网 (ER)应激反应我们的中心假设是苯诱导的小胶质细胞的变化 功能和IKKβ/NF-κB信号转导是全身葡萄糖稳态变化的基础， 代谢反应这一假设将评估与一种新的小鼠模型的空气污染 结合分子，遗传和生理方法，旨在操纵这两个 在以下特定的情况下，常驻小胶质细胞的数量和炎症激活状态 目的：1）确定接触低浓度苯对 研究IKKβ/NF-κB在神经炎症和代谢调节中的作用 苯诱导的代谢失衡中的炎症机制：3）确定细胞 以及小胶质细胞神经炎症和内质网应激反应之间的分子相互作用， 苯暴露。这项拟议的研究将首次直接评估 苯诱导的胶质细胞功能和炎症信号调节全身的变化 新陈代谢.这样的研究将对制定公共卫生政策具有重要意义， 苯暴露及其在易患代谢性疾病中的作用。